Evolutionary implications of human transmission of monkeypox: the importance of sequencing multiple lesions
Authors: David O Ulaeto, Jake Dunning, Miles W Carroll
Journal: The Lancet Microbe (2022)

The international outbreak of monkeypox that was recognised in May, 2022 represents a new transmission route for monkeypox virus. Since it was first recognised as a zoonotic pathogen in the 1970s, this virus has frequently jumped from its rodent reservoir hosts into people, predominantly in the Democratic Republic of the Congo. Such zoonotic events are estimated at several thousand per year, but are characterised by low human-to-human transmission.1Bunge EM Hoet B Chen L et al.The changing epidemiology of human monkeypox—a potential threat? A systematic review.PLoS Negl Trop Dis. 2022; 16e0010141Crossref PubMed Scopus (695) Google Scholar, 2Rimoin AW Mulembakani PM Johnston SC et al.Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo.Proc Natl Acad Sci USA. 2010; 107: 16262-16267Crossref PubMed Scopus (439) Google Scholar In the Democratic Republic of the Congo, zoonosis is predominantly seen in school-age boys in rural areas, who engage in hunting small game.3Nolen LD Osadebe L Katomba J et al.Introduction of monkeypox into a community and household: risk factors and zoonotic reservoirs in the Democratic Republic of the Congo.Am J Trop Med Hyg. 2015; 93: 410-415Crossref PubMed Scopus (76) Google Scholar By contrast, the outbreak that began in Nigeria in 2017 predominantly involved men aged 25–40 years in urban or periurban areas, with no obvious connection to suspected animal reservoirs.4Ogoina D Iroezindu M James HI et al.Clinical course and outcome of human monkeypox in Nigeria.Clin Infect Dis. 2020; 71: e210-e214Crossref PubMed Scopus (221) Google Scholar The presentation of monkeypox in the current outbreak is also new. Traditionally, human monkeypox presents as a generalised monomorphic pustular rash, and genital lesions are rare.5Ježek Z Fenner F Human monkeypox. Karger Publishers, Basel1988Google Scholar, 6Huhn GD Bauer AM Yorita K et al.Clinical characteristics of human monkeypox, and risk factors for severe disease.Clin Infect Dis. 2005; 41: 1742-1751Crossref PubMed Scopus (325) Google Scholar, 7Ježek Z Szczeniowski M Paluku K Mutombo M Human monkeypox: clinical features of 282 patients.J Infect Dis. 1987; 156: 293-298Crossref PubMed Scopus (337) Google Scholar In the current international outbreak, including in Nigeria, an ulcerating genital rash develops in the majority of cases. For clinical presentations outside Africa, the genital rash precedes the generalised pustular rash, which is often minor.4Ogoina D Iroezindu M James HI et al.Clinical course and outcome of human monkeypox in Nigeria.Clin Infect Dis. 2020; 71: e210-e214Crossref PubMed Scopus (221) Google Scholar, 8Antinori A Mazzotta V Vita S et al.Epidemiological, clinical and virological characteristics of four cases of monkeypox support transmission through sexual contact, Italy, May 2022.Euro Surveill. 2022; 272200421Crossref PubMed Scopus (303) Google Scholar, 9Vaughan A Aarons E Astbury J et al.Two cases of monkeypox imported to the United Kingdom, September 2018.Euro Surveill. 2018; 231800509Crossref PubMed Scopus (226) Google Scholar, 10Erez N Achdout H Milrot E et al.Diagnosis of imported monkeypox, Israel, 2018.Emerg Infect Dis. 2019; 25: 980-983Crossref PubMed Scopus (217) Google Scholar, 11Hammerschlag Y MacLeod G Papadakis G et al.Monkeypox infection presenting as genital rash, Australia, May 2022.Euro Surveill. 2022; 272200411Crossref PubMed Scopus (98) Google Scholar, 12Duque MP Ribeiro S Martins JV et al.Ongoing monkeypox virus outbreak, Portugal, 29 April to 23 May 2022.Euro Surveill. 2022; 272200424PubMed Google Scholar This presentation suggests that the genital area is a site of primary infection, giving rise to a localised rash, which is then sometimes followed by a secondary disseminated infection. Interestingly, reports from Nigeria up to 2020 and the USA in 2003 describe most patients as having monomorphic lesions, whereas in the current outbreak clinicians in the UK anecdotally report predominantly pleiomorphic lesions at different stages of eruption at the same time. In the current outbreak, monkeypox virus seems to be transmitting via a primary localised rash (appendix). Transmission via primary rash (primary transmission) removes the requirement for the virus to establish a general disseminated infection, and this could facilitate the evolution of variants. Such a transmission route could also facilitate the co-transmission of multiple variants, as primary lesions avoid the bottleneck of secondary dissemination. If monkeypox virus is adapting to human transmission by this novel route, the adaptations should most readily be seen in genomes that are sequenced from primary rash lesions. Although transmission outside central Africa might be predominantly via primary rash, secondary disseminated rashes are still observed. If multiple genomes are transmitted via the primary rash, then the current situation could involve the co-transmission of two syndromes—a localised or primary monkeypox and a generalised or secondary monkeypox—that have different in-host selection pressures and pose different transmission hazards. Although both syndromes are initially caused by the same virus, primary monkeypox is expected to favour variants that are adapted for primary transmission, whereas generalised monkeypox would favour variants that are capable of disseminated infection. Importantly, primary transmission chains are likely to be accelerated relative to transmissions via secondary rash. Also, if the current international spread reflects, or facilitates, adaptation for primary transmission, the incidence of disseminated infections might reduce over time. A reduction in disseminated infections would reduce the risk of transmission by fomites or droplets, but might also lead to a higher proportion of unrecognised infections, increasing the difficulty of breaking the transmission chain. Additionally, if primary transmission facilitates variants that are better adapted to this transmission route, we might expect further evolution as adaptation to humans is refined by natural selection. Monitoring by health authorities for the emergence of variants that are adapted for primary transmission is therefore important. In generalised rashes caused by Orthopoxvirus species, each lesion is thought to be clonal.13Li G Chen N Feng Z et al.Genomic sequence and analysis of a vaccinia virus isolate from a patient with a smallpox vaccine-related complication.Virol J. 2006; 3: 88Crossref PubMed Scopus (22) Google Scholar, 14Qin L Upton C Hazes B Evans DH Genomic analysis of the vaccinia virus strain variants found in Dryvax vaccine.J Virol. 2011; 85: 13049-13060Crossref PubMed Scopus (57) Google Scholar As such, a genome sequence taken from a single lesion might not be representative of the population within the patient, although this might not be the case for lesions that represent a primary focus of infection. If viruses closer to the zoonotic parent are more fit for disseminated infection, then we will expect to see more of these parental sequences recovered from secondary rash lesions, and a higher proportion of adaptive mutations in genomes recovered from primary rash lesions. To gain a full understanding of the evolution and adaptation of monkeypox virus in this international outbreak, sequencing genomes from multiple lesions from both the primary and secondary rash of individual patients is of crucial importance. In practical terms, and particularly in the current outbreaks in Europe, this approach could mean sampling genital and perianal lesions in addition to lesions elsewhere on the body. Studies such as the ISARIC–WHO Clinical Characterisation Protocol for Severe Emerging Infections,15International Severe Acute Respiratory and Emerging Infection ConsortiumMonkeypox response.https://isaric.org/research/monkeypox-response/Date accessed: June 14, 2022Google Scholar which was recently adapted for monkeypox, provide opportunities to obtain longitudinal samples from multiple sites and compartments for virus characterisation. Such an approach enables the comparison of longitudinal virology results with respective exposure histories and clinical descriptions of the rash illness, to explore hypotheses about primary and secondary transmission. We declare no competing interests. Download .pdf (.28 MB) Help with pdf files Supplementary appendix